NM_003289.4:c.115-105A>G

Variant names:

• chr9-35689376-T-C
• rs2145925
• NM_003289.4:c.115-105A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003289.4(TPM2):​c.115-105A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.443 in 1,545,900 control chromosomes in the GnomAD database, including 153,369 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (15688 hom., cov: 33)
  • Exomes 𝑓: 0.44 (137681 hom.)
• Consequence: TPM2 NM_003289.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -1.84

Genes affected

TPM2 (HGNC:12011): (tropomyosin 2) This gene encodes beta-tropomyosin, a member of the actin filament binding protein family, and mainly expressed in slow, type 1 muscle fibers. Mutations in this gene can alter the expression of other sarcomeric tropomyosin proteins, and cause cap disease, nemaline myopathy and distal arthrogryposis syndromes. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 9-35689376-T-C is Benign according to our data. Variant chr9-35689376-T-C is described in ClinVar as [Benign]. Clinvar id is 140484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35689376-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM2	NM_003289.4	c.115-105A>G		intron_variant	Intron 1 of 8	ENST00000645482.3	NP_003280.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM2	ENST00000645482.3	c.115-105A>G		intron_variant	Intron 1 of 8		NM_003289.4	ENSP00000496494.2

Frequencies

GnomAD3 genomes AF: 0.453 AC: 68785 AN: 151966 Hom.: 15675 Cov.: 33

Gnomad AFR AF: 0.473

Gnomad AMI AF: 0.576

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.626

Gnomad SAS AF: 0.491

Gnomad FIN AF: 0.474

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.433

Gnomad OTH AF: 0.460

GnomAD4 exome AF: 0.442 AC: 616701 AN: 1393816 Hom.: 137681 Cov.: 34 AF XY: 0.444 AC XY: 305766 AN XY: 688726

Gnomad4 AFR exome AF: 0.472

Gnomad4 AMR exome AF: 0.360

Gnomad4 ASJ exome AF: 0.455

Gnomad4 EAS exome AF: 0.626

Gnomad4 SAS exome AF: 0.490

Gnomad4 FIN exome AF: 0.479

Gnomad4 NFE exome AF: 0.433

Gnomad4 OTH exome AF: 0.444

GnomAD4 genome AF: 0.453 AC: 68826 AN: 152084 Hom.: 15688 Cov.: 33 AF XY: 0.454 AC XY: 33761 AN XY: 74334

Gnomad4 AFR AF: 0.472

Gnomad4 AMR AF: 0.393

Gnomad4 ASJ AF: 0.454

Gnomad4 EAS AF: 0.626

Gnomad4 SAS AF: 0.492

Gnomad4 FIN AF: 0.474

Gnomad4 NFE AF: 0.433

Gnomad4 OTH AF: 0.463

Alfa AF: 0.436 Hom.: 14202

Bravo AF: 0.449

Asia WGS AF: 0.577 AC: 2008 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

TPM2 homepage - Leiden Muscular Dystrophy pages

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.1
DANN	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2145925; hg19: chr9-35689373; COSMIC: COSV61407066; COSMIC: COSV61407066;